An E2F/miR-20a Autoregulatory Feedback Loop*

The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1–3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17–92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17–92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3′-untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17–92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17–92 cluster. Our data also point toward an anti-apoptotic role for miR-20a, since overexpression of this miRNA decreased apoptosis in a prostate cancer cell line, while inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin treatment. This anti-apoptotic role of miR-20a may explain some of the oncogenic capacities of the mir-17–92 cluster. Altogether, these results suggest that the autoregulation between E2F1–3 and miR-20a is important for preventing an abnormal accumulation of E2F1–3 and may play a role in the regulation of cellular proliferation and apoptosis.

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